Pharmacological profile of astemizole-derived compounds at the histamine H1 and H4 receptor—H1/H4 receptor selectivity

Astemizole, a H 1 R antagonist shows high affinity to the histamine H 1 receptor but only a moderate affinity to the histamine H 4 receptor. This study aims to modify the astemizole to keep high affinity to the histamine H 1 receptor and to increase affinity to the histamine H 4 receptor. Therefore, 13 astemizole-derived compounds and astemizole-JNJ7777120-derived hybrid compounds were synthesized and pharmacologically characterized at the histamine H 1 and H 4 receptors. The new compounds show affinity to the histamine H 1 receptor in the p K i range from 5.3 to 8.8, whereas the affinity of these compounds to the histamine H 4 receptor was surprisingly rather low (p K i from 4.4 to 5.6). Three representative compounds were docked into the histamine H 1 receptor and molecular dynamic studies were performed to explain the binding mode and the experimental results on a molecular level. Furthermore, taking into account the binding mode of compounds with high affinity to the histamine H 4 receptor, a H 1 /H 4 -pharmacophore hypothesis was developed.